Bifunctional Naphtho[2,3- d][1,2,3]triazole-4,9-dione Compounds Exhibit Antitumor Effects In Vitro and In Vivo by Inhibiting Dihydroorotate Dehydrogenase and Inducing Reactive Oxygen Species Production

Zeping Zuo; Xiaocong Liu; Xinying Qian; Ting Zeng; Na Sang; Huan Liu; Yue Zhou; Lei Tao; Xia Zhou; Na Su; Yamei Yu; Qiang Chen; Youfu Luo; Yinglan Zhao

doi:10.1021/acs.jmedchem.0c00512

Bifunctional Naphtho[2,3- d][1,2,3]triazole-4,9-dione Compounds Exhibit Antitumor Effects In Vitro and In Vivo by Inhibiting Dihydroorotate Dehydrogenase and Inducing Reactive Oxygen Species Production

J Med Chem. 2020 Jul 23;63(14):7633-7652. doi: 10.1021/acs.jmedchem.0c00512. Epub 2020 Jul 1.

Authors

Zeping Zuo¹, Xiaocong Liu¹, Xinying Qian¹, Ting Zeng¹, Na Sang¹, Huan Liu¹, Yue Zhou¹, Lei Tao¹, Xia Zhou¹, Na Su², Yamei Yu¹, Qiang Chen¹, Youfu Luo¹, Yinglan Zhao^{1

3}

Affiliations

¹ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
² Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610041, China.
³ West China School of Pharmacy, Sichuan University, Chengdu 610041, China.

PMID: 32496056
DOI: 10.1021/acs.jmedchem.0c00512

Abstract

Human dihydroorotate dehydrogenase (hDHODH) is an attractive target for cancer therapy. Based on its crystal structure, we designed and synthesized a focused compound library containing the structural moiety of 1,4-benzoquinone, which possesses reactive oxygen species (ROS) induction capacity. Compound 3s with a naphtho[2,3-d][1,2,3]triazole-4,9-dione scaffold exhibited inhibitory activity against hDHODH. Further optimization led to compounds 11k and 11l, which inhibited hDHODH activity with IC₅₀ values of 9 and 4.5 nM, respectively. Protein-ligand cocrystal structures clearly depicted hydrogen bond and hydrophobic interactions of 11k and 11l with hDHODH. Compounds 11k and 11l significantly inhibited leukemia cell and solid tumor cell proliferation and induced ROS production, mitochondrial dysfunction, apoptosis, and cell cycle arrest. Nanocrystallization of compound 11l displayed significant in vivo antitumor effects in the Raji xenograft model. Overall, this study provides a novel bifunctional compound 11l with hDHODH inhibition and ROS induction efficacy, which represents a promising anticancer lead worthy of further exploration.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Dihydroorotate Dehydrogenase
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / pharmacology*
Female
Humans
Male
Membrane Potential, Mitochondrial / drug effects
Mice, Inbred BALB C
Mice, SCID
Molecular Docking Simulation
Molecular Structure
Naphthoquinones / chemical synthesis
Naphthoquinones / metabolism
Naphthoquinones / pharmacokinetics
Naphthoquinones / pharmacology*
Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
Oxidoreductases Acting on CH-CH Group Donors / metabolism
Protein Binding
Rats, Sprague-Dawley
Reactive Oxygen Species / metabolism*
S Phase Cell Cycle Checkpoints / drug effects
Structure-Activity Relationship
Triazoles / chemical synthesis
Triazoles / metabolism
Triazoles / pharmacokinetics
Triazoles / pharmacology*

Substances

Antineoplastic Agents
Dihydroorotate Dehydrogenase
Enzyme Inhibitors
Naphthoquinones
Reactive Oxygen Species
Triazoles
Oxidoreductases Acting on CH-CH Group Donors